Citations for all references are found after the experimental section.
Mesial temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults (Engel, 1989), and frequently becomes resistant to drug therapy, leaving ultimately only a neurosurgery option to control seizures. TLE develops following a variety of insults, including brain injury and status epilepticus (SE). Precipitating insults are followed by a characteristic seizure-free “latent period” lasting typically a few months, in exceptional cases even years, in humans (Annegers et al., 1980; Weiss et al., 1986). The TLE in rats that arises several weeks after a lithium-pilocarpine induced SE reproduces most clinical and neuropathological features of human TLE, and presents a very useful animal model of the disease (Ormandy et al., 1989; Turski et al., 1991; Cavalheiro, 1995; Dube et al., 2000; Andre et al., 2007). Even though initial causes may vary, the behavioral and histo-pathological hallmarks of TLE are remarkably similar in all etiologies. This has led a number of investigators to hypothesize that there is a major common pathway downstream of initiating causes, probably the intense synchronous activity that is a signature of seizures (Du et al., 1995; Wu and Schwarcz, 1998; Schwarcz et al., 2000). This synchronous activity is usually seen in hippocampus and parahippocampal cortices, including the EC (Schwartzkroin and Knowles, 1984; Bartolomei et al., 2004). Over the longer term, specific mesial temporal lobe atrophy has been shown ipsilateral to the seizure focus (Bartolomei et al., 2005). Examination of surgically resected specimens has revealed cell loss and astrogliosis in EC (Yilmazer-Hanke et al., 2000).
Exactly where important early changes in neuronal physiology occur after the SE is unclear; however, neuroprotection experiments of hippocampal Cornu Ammonis (CA) regions vs. parahippocampal cortices suggest a key role of the parahippocampal cortices at the early steps of epileptogenesis (Andre et al., 2007). Moreover, we have observed in previous studies that the deep EC exhibits unusual high network excitation, in striking contrast to layers 2 and 3 (Gloveli et al., 1999; Egorov et al., 2003), suggesting that the deep EC may be particularly susceptible to the development of hyperexcitability triggered by status epilepticus.
An important mechanism in preventing spontaneously recurring seizures (SRS) is Cl-dependent synaptic inhibition of excitatory neurons. The effectiveness of this inhibition decreases with an increase in intracellular Cl-relative to extracellular Cl-concentration. The intracellular Cl-concentration is decreased by K+Cl-co-transporters, particularly KCC2, driven by the K+ outward gradient, and increased by Na+K+2Cl-co-transporters, particularly NKCC1, driven by the Na+ inward gradient. Thus it is well established for peripheral and central neurons that both Cl-transports play an important role for efficiency of synaptic inhibition (Aickin et al., 1984; Misgeld et al., 1986).
U.S. Patent Application Document No. 20070043034 describes the use of diuretic compounds to treat various disorders, in particular sodium potassium chloride cotransport mediated disorders, and disorders associated with excitotoxicity in the brain that are exacerbated by impaired inhibition of gamma aminobutyric acid (GABA).
Notwithstanding efforts to prevent or treat TLE, the need continues to exist for methods of treatment which will prevent or ameliorate the aforementioned TLE-related insults.